Pharmacology Of Diabetes

Question 1

What is the primary mechanism of action of Metformin?

Answer 1

Primary effect – metformin activates AMPK in hepatocyte mitochondria - inhibits ATP production, blocking gluconeogenesis and subsequent glucose output
Also blocks adenylate cyclase which promotes fat oxidation
Both help to restore insulin sensitivity

Question 2

What is the drug target of Metformin?

Answer 2

5′-AMP-activated protein kinase (AMPK)

The primary site of metformin action is the hepatocyte mitochondria

Question 3

What are the main side effects of Metformin?

Answer 3

GI side effects (20-30% of patients)
e.g. abdominal pain, decreased appetite, diarrhoea, vomiting

Question 4

When are side effects of Metformin particularly evident and how can this be addressed?

Answer 4

Particularly evident when very high doses are given
A slow increase in dose may improve tolerability

Question 5

Why does Metformin require a transporter to access tissues?

Answer 5

Highly polar

Question 6

What transporter is required for Metformin to access tissues?

Answer 6

Organic cation transporter-1 (OCT-1)

Question 7

Why can Metformin accumulate in the liver (therapeutic effect) and gastrointestinal tract (side effects)?

Answer 7

Because it requires the OCT-1 transporter (expressed by liver, small bowel and kidney) to access tissues

Question 8

When is Metformin most effective?

Answer 8

Metformin is most effective in the presence of endogenous insulin so is most effective with some residual functioning pancreatic islet cells

Question 9

Give an example of a DPP-4 inhibitor

Answer 9

Sitagliptin

Question 10

What is the primary mechanism of action of DPP-4 inhibitors?

Answer 10

Work by inhibiting the action of dipeptidyl-peptidase 4 (DPP-4)
This enzyme is present in vascular endothelium and can metabolise incretins in the plasma

Question 11

What do incretins do?

Answer 11

Incretins (e.g. GLP-1) are secreted by enteroendocrine cells:
- help stimulate the production of insulin when it is needed (e.g. after eating)
- reduce the production of glucagon by the liver when it is not needed (e.g. during digestion)
- also slow down digestion and decrease appetite

Question 12

What is the drug target of DPP-4 inhibitors?

Answer 12

DPP-4

The primary site of DPP-4 inhibitor action is the vascular endothelium

Question 13

What are the main side effects of DPP-4 inhibitors?

Answer 13

Upper respiratory tract infections (5% of patients)
Flu-like symptoms e.g. headache, runny nose, sore throat

Less common but serious:
Serious allergic reactions
Avoid in patients with pancreatitis

Question 14

Do DPP-4 inhibitors appear to cause weight gain?

Answer 14

No, unlike other anti-diabetic drugs (not Metformin)

Question 15

Would DPP-4 inhibitors be effective in patients with no residual insulin?

Answer 15

No
DPP-4 I’s act mainly by augmenting insulin secretion -> effective only when some residual pancreatic beta-cell activity is present

Question 16

What is an example of a sulphonylurea?

Answer 16

Gliclazide

Question 17

What is the primary mechanism of action of sulphonylurea?

Answer 17

Inhibits the ATP-sensitive potassium (KATP) channel on the pancreatic beta cell -> controls beta cell membrane potential
Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

Question 18

What is the drug target of sulphonylureas?

Answer 18

ATP-sensitive potassium channel

The primary site of SUs inhibitor action is the pancreatic beta cell

Question 19

What are the main side effects of sulphonylureas?

Answer 19

Weight gain is a likely side effect
Hypoglycaemia (2nd most common)

Question 20

Why are SUs only effective when there is some residual pancreatic beta cell activity?

Answer 20

Act mainly by augmenting insulin secretion

Question 21

How is weight gain mitigated when taking sulphonylureas?

Answer 21

Mitigated by concurrent administration with Metformin

Question 22

Give an example of an SGLT2 inhibitor

Answer 22

Dapaglifozin

Question 23

What is the main mechanism of action of SGLT2 inhibitors?

Answer 23

Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion

Question 24

What is the primary target of SGLT2 inhibitors?

Answer 24

SGLT2

The primary site of SGLT2 inhibitor action is the proximal convoluted tubule

Question 25

What are the main side effects of SGLT2 inhibitors?

Answer 25

Uro-genital infections due to increased glucose load (5% of patients)
Slight decrease in bone formation
Can worsen diabetic ketoacidosis (stop immediately)

Question 26

In which condition are SGLT2 inhibitors less effective?

Answer 26

Renal impairment
SGLT2i action depends on normal renal function

Question 27

What other effects do SGLT2 inhibitors have on the body?

Answer 27

Weight loss
Reduction in BP

Question 28

What is the relevance of OCT-1 expression in hepatocytes, enterocytes and proximal tubules to the pharmacokinetics of orally administered Metformin?

Answer 28

Small bowel OCT-1 allows absorption
Hepatocytes OCT-1 allows distribution to site of action
Proximal tubule OCT-1 helps excretion